Genetics of Human Hypertension

BACKGROUND: Hypertension is a multifactorial disease involving interactions among genetic, environmental, demographic, vascular and neuroendocrine factors. Essential hypertension is the most frequent diagnosis in this syndrome, indicating that a monocausal etiology has not been identified. However, a number of risk factors underlying essential hypertension have also been identified including age, sex, genetics, demographic factors, and others. Remarkable progress in molecular biological research has been achieved in clarifying the molecular basis of Mendelian hypertensive disorders. Causative genes and chromosomal fragments harboring disease susceptibility genes have been identified, e. g., for glucocorticoid-remediable aldosteronism, Liddle's syndrome, mineralocorticoid excess. MOLECULAR GENETIC STUDIES: Molecular genetic studies have now identified mutations in eight genes that cause Mendelian forms of hypertension and nine genes that cause Mendelian forms of hypotension in humans. No single genetic variant has emerged from linkage or association analyses as consistently related to blood pressure level in every sample and in all populations. However, a number of polymorphisms in candidate genes have been associated with differences in blood pressure. Most prominent have been the polymorphisms in the renin-angiotensin-aldosterone system. CONCLUSION: Essential hypertension is likely to be a polygenic disorder that results from the inheritance of a number of susceptibility genes and involves multiple environmental determinants. These determinants complicate the study of blood pressure variations in the general population. The complex nature of the hypertension phenotype makes large-scale studies indispensable, when screening of familial and genetic factors is intended.     

原发性高血压的基因机制-RAAS系统基因多态性

原发性高血压(EH)是遗传和环境因素相互作用所致的多因素疾病,对其基因机制的研究有助于从分子水平探讨EH的发病机制.近年来对于EH候选基因多态性的研究逐渐增多,本文即对肾素-血管紧张素-醛固酮系统(RAAS)基因多态性与EH之间的关系的研究进展作一综述.     

Genetic determinants of hypertension: An update

Hypertension represents a global public health burden. In addition to the rarer Mendelian forms of hypertension, classic genetic studies have documented a significant heritable component to the most common form, essential hypertension (EH). Extensive efforts are under way to elucidate the genetic basis of this disease. Recently, a new form of Mendelian hypertension has been identified, pharmacogenetic association studies in hypertensive patients have identified novel gene-by-drug interactions, and the first genome-wide association studies of EH have been published. New findings in consomic and congenic rat models also offer new clues to the genetic architecture of this complex phenotype. In this review, the authors summarize and evaluate the most recent findings related to hypertension gene identification.     

The kidney and hypertension: lessons from mouse models

The pathogenesis of hypertension is multi-factorial, involving many of the systems contributing to blood pressure homeostasis including the vasculature, kidneys, central, and sympathetic nervous systems, along with various hormonal regulators. However, over the years, many studies have indicated a predominant importance of the kidney in blood pressure homeostasis and hypertension. This work has established the notion that the kidney is a key determinant of the chronic level of intra-arterial pressure playing a major role in the pathogenesis of hypertension. Therefore, this review will focus on recent work using genetically modified mouse models addressing the role of the kidney in hypertension. In particular, human genetic studies of Mendelian disorders with major impact on blood pressure homeostasis have provided powerful evidence for a role of the kidney in hypertension. Of the approximately 20 genes identified as causal in these disorders, virtually all have an effect on the control of solute transport in the kidney. As such, we have especially focused on generation of mouse models addressing the nature of these specific molecular defects in nephron function that produce an alteration in blood pressure.     

The genetic basis of essential hypertension

During the last few years the studies on the genetic basis of essential hypertension (EH) have been numerous, allowing however only a partial understanding of the underlying molecular mechanisms. The most used techniques were the candidate gene approach, genome-wide scanning, the intermediate phenotype approach and comparative-genomics in animal models. The renin-angiotensin-aldosterone system may play a prominent role in the genesis of hypertension, and polymorphisms of the genes coding for angiotensinogen, angiotensin-converting enzyme, angiotensin II type 1 and 2 receptors, and aldosterone synthase have been widely studied. Other mechanisms may involve the KLK 1 gene of tissue kallikrein, gene variants of endothelial nitric oxide synthase and polymorphisms of the endothelin-1 gene. Finally, a number of studies have highlighted the potential contribution of polymorphisms of genes coding for inflammatory cytokines, adrenergic receptors and intracellular G proteins, which can activate Na+/K+ exchangers. Further important information might derive from proteomic analysis and the study of mitochondrial genome. Overall, results have often been discordant, sometimes suggesting a different expression of the same gene variants in different populations. EH is a highly polygenic condition, caused by the combination of small changes in the expression of many genes, in conjunction with a variable collection of environmental factors.     

Can the genetic factors influence the treatment of systemic hypertension? The case of the renin-angiotensin-aldosterone system.

The hereditary nature of familial hypertension has been clearly established by a number of clinical studies. About 30% of the blood pressure variance can be attributed to genetic factors. As a consequence, the relative risk for developing coronary artery disease or cardiovascular death is increased in patients with a family history of hypertension and cardiovascular disease. Patients with such familial history should be considered at the same risk as those who have independent epidemiologic risk factors. The development of molecular genetics allows establishment of a link between high blood pressure, intermediate phenotypes, and the genes involved in blood pressure regulation. Gene markers should be available in the near future that will help to identify patients predisposed to hypertension. The genes of the renin-angiotensin-aldosterone system are good examples of candidate genes whose products are known to participate in blood pressure regulation. The possible involvement of these genes in essential hypertension is critically analyzed.     

Roles of catecholamine related polymorphisms in hypertension

The objective of this review is to summarize current data obtained so far in catecholamine-essential hypertension (EH) relationships on a genetic basis. As the major elements driving the sympathetic system’s actions, catecholamines modulate a variety of physiological processes and mutations related to the system. This could generate serious disorders, such as severe mental illnesses, stress-induced disorders, or impaired control of blood pressure or motor pathways. EH is idiopathic, and the genetic basis of its causes and substantial interindividual discrepancies in response to different types of treatments are the focus of interest. Susceptibility to disease or efficacy of treatments are thought to reflect genomic variabilities among individuals. Therefore, outlining the available knowledge in functional genetic polymorphisms linked to EH will make the picture clearer and will help to establish future prospects in the field.     

Pharmacogenomics of blood pressure response to antihypertensive treatment

PURPOSE IDENTIFICATION: Inter-individual variability in blood pressure response to treatment is well documented, but a clinically useful means to distinguish responders from non-responders has been elusive. With the advent of new technologies and genomic knowledge, more investigators are seeking to identify genetic determinants of blood pressure response to therapy. STUDY SELECTION: We identified studies of candidate polymorphisms from an initial PubMed search using the MESH terms 'Hypertension: Drug Therapy' and 'Genetics' or 'Pharmacogenetics', limiting results to English-language publications on studies in human adults. We further identified specific polymorphisms of interest noted in earlier reviews and performed additional PubMed searches based on these candidate genes. Pertinent studies were further extracted from the references of studies already identified. We focused on clinical trials that measured blood pressure response to a medication or class of medications over a minimum of 4 weeks. DATA EXTRACTION: We evaluated studies looking at blood pressure response to commonly used classes of antihypertensive medications by major genetic variants. RESULTS OF ANALYSIS: Although many studies show that blood pressure response to a given class of antihypertensive medications varies by genotype for different polymorphisms, none of the genotypes identified consistently predicted blood pressure response. CONCLUSIONS: Common variants may influence response to diuretics, beta-blockers, angiotensin-converting enzyme inhibitors, and angiotensin receptor blockers, but studies of polymorphisms have generally yielded conflicting results. The inclusion of pharmacogenomic studies in large clinical trials and other more innovative investigative methods may provide greater clarity of the potential role for genotyping in the treatment of patients with hypertension.     

Genetic determinants of arterial thrombosis

Arterial thrombosis is a complex disorder that involves multiple genetic and environmental factors interacting to produce the characteristic phenotype. In the past decades, investigators have focused on the molecular genetics of arterial vascular disorders and have identified numerous polymorphisms and mutations in genes related to the hemostatic system and to enzymes involved in the synthesis and bioavailability of nitric oxide (NO); however, the relation between most polymorphisms and the risk of coronary artery disease, ischemic stroke, and peripheral vascular disease remains highly controversial. In this review, we describe the most common genetic variations involved in the pathogenesis of arterial thrombosis, their functional implications, and their association with disease risk. Specifically, we consider polymorphisms in coagulation factors (fibrinogen, prothrombin, FV Leiden, FVII, and FXIII); fibrinolytic factors (tissue-type plasminogen activator, plasminogen activator inhibitor-1, and thrombin-activatable fibrinolysis inhibitor); platelet surface receptors; methylenetetrahydrofolate reductase; endothelial NO synthase; and the antioxidant enzymes paraoxonase and plasma glutathione peroxidase. Overall, there seems to be a modest contribution of individual genetic variants in the hemostatic and antioxidant systems to the risk of arterial thrombosis. Thus, future research ought to focus on identifying novel genetic determinants and on the interaction of these genetic risk factors with each other and the environment to understand better the pathobiology and susceptibility to arterial thrombotic disease.     

Hypertension and single nucleotide polymorphisms

Hypertension is a common, complex disease phenotype that has been intensively studied to identify susceptibility loci in humans. Candidate genes continue to be uncovered via genetic analysis in model organisms through linkage analysis with families and/or sib-pairs and through association studies using sequence variants in genes that play a role in key pathways regulating blood pressure in humans, such as the renin-angiotensin system (RAS). Recent studies exploring the sequence diversity in human candidate genes suggest that the distribution and organization of single nucleotide polymorphisms (SNPs) within and among human populations is complex. Issues related to the use of SNPs in analyzing the genetic determinants of hypertension are illustrated using recent studies on the angiotensin-converting enzyme (ACE).     

Le lupus systémique à début pédiatrique : une pathologie polygénique ou monogénique ?

Systemic lupus erythematosus (SLE) results from the complex interaction between genetic and environmental factors. It is usually thought that SLE results from the combined effect of variants in a large number of genes, and several genome whole association studies (GWAS) have identified a great number of single-nucleotide polymorphisms (SNP) associated with SLE. However, the loci identified so far can account for only about 15% of the heritability of SLE. Recently, some Mendelian variants of lupus have been identified, especially in childhood-onset SLE. Children present with more severe illness, a lower sex-ratio female:male and a higher genetic contribution compared to adults with SLE. pSLE phenotype heterogeneity could be related to genetic heterogeneity, and pSLE in part might consist in a collection of rare, genetically distinct monogenic disorders.     

Transgenic and knockout mice to study the renin-angiotensin system and other interacting vasoactive pathways

Essential hypertension is an insidious disease in which the afflicted person risks disability and death from myocardial infarction and stroke. Many factors contribute to the development of essential hypertension, including environment, diet, daily stress, and genetics. Although several single gene disorders causing high blood pressure have been identified, the genetics of essential hypertension are much more complicated. The current hypothesis is that a combination of genetic variations in multiple genes may predispose a person to hypertension. Both overexpression and gene inactivation ("knockout") have proven useful tools to evaluate the genetics of essential hypertension and to identify pathways regulating blood pressure. Molecular and physiologic evaluations of transgenic and knockout mice carried out over the past 5 years have provided a plethora of information about the mechanisms of blood pressure regulation and the development and maintenance of hypertension. This review focuses on the newer mouse models that have been developed to investigate hypertension with an emphasis on vascular and renal mechanisms, contributed by the renin-angiotensin system, and other pathways intersecting with the renin-angiotensin system.     

The genetic architecture of blood pressure variation

High blood pressure affects over 1 billion people worldwide and is responsible for 50% of all cardio vascular deaths. Despite numerous candidate gene and linkage studies, no susceptibility loci for hypertension have been robustly validated except for rare monogenic disorders. Recent large meta-analyses of genome-wide association scans, however, have changed the situation. Thirteen new hypertension loci have now been described, many of which have strong biological candidates. All associated variants have common allele frequencies and exert modest to small effects on disease risk. Rare and low frequency variants with larger effect sizes in genes causing monogenic disorders have also been found, suggesting blood pressure heritability may be explained in part by a combination of both common and rare genetic variants. It is hoped these new findings will pave the way for a better understanding of blood pressure regulation and offer the potential to develop new treatments that may prevent heart disease and stroke.     

Association of alpha-adducin Gly460Trp polymorphism with coronary artery disease in a Korean population

OBJECTIVE: Coronary artery disease is caused by multiple genetic and environmental factors. The disease is also closely associated with cardiovascular conditions such as hypertension. In order to investigate any possible role of hypertension candidate genes in the disease development and progression, we examined the association of the polymorphisms of 31 hypertension candidate genes with coronary artery disease. METHODS: Genetic polymorphisms of 31 hypertension candidate genes were initially screened by resequencing DNA samples from 24 unrelated individuals in a Korean population. Association analysis was performed using 1284 unrelated Korean men, including 749 coronary artery disease subjects and 535 normal healthy controls. RESULTS: We identified a total of 409 single nucleotide polymorphisms including 40 nonsynonymous single nucleotide polymorphisms, 32 insertions/deletions and four microsatellites. Among 40 nonsynonymous single nucleotide polymorphisms, 29 were examined for an association with coronary artery disease. A significant association with coronary artery disease was observed in a polymorphism of the ADD1 gene (Gly460Trp; +29017G/T) (odds ratio 0.71-0.81; P = 0.01-0.04). The same polymorphism was also associated with the number of arteries with significant coronary artery stenosis in the coronary artery disease patients (P = 0.01) as well as the increase in systolic blood pressure (P = 0.02). CONCLUSIONS: The ADD1 Gly460Trp polymorphism is significantly associated with an increased risk of coronary artery disease as well as blood pressure, indicating that ADD1 plays a role in the pathogenesis of coronary artery disease as well as hypertension.     

Investigation of major genetic polymorphisms in the Renin-Angiotensin-aldosterone system in subjects with young-onset hypertension selected by a targeted-screening system at university

Although polymorphisms in renin-angiotensin-aldosterone (RAA) system genes for angiotensinogen (AGT M235T), angiotensin-converting enzyme (ACE I/D), angiotensin II type 1 receptor (AT1 A/C1166), and aldosterone synthase (CYP11B2-344T/C) have been major targets for genetic investigation in association with essential hypertension (EH), the influence of these genetic factors is still to be determined. Because patients with young-onset EH are thought to possess a stronger genetic background than EH patients who show elevated BP relatively late in life, the targeted screening of hypertensive students in Tohoku University was completed for the selection of subjects for genetic investigation. Out of 16,434 students (12,794 males and 3,670 females) younger than 30, 22 students showed a high blood pressure (BP) (systolic and diastolic BP of 140 and/or 90 mmHg or greater, respectively, on two occasions and more than 135 and/or 85 mmHg, respectively, at a third measurement during casual BP measurements at the Tohoku University Health Center. These 22 students were asked to measure their BP at home (HBP). Six of the students had a systolic HBP of more than 135 mmHg and/or a diastolic HBP of more than 85 mmHg, and these students subsequently received medical examinations at Tohoku University Hospital and were diagnosed with EH. Genotyping for the four major genetic polymorphisms mentioned above was performed on the six students with EH and on 12 of the remaining 16 students whose HBP was within the normal range (white coat hypertension: WCH). Neither the EH nor the WCH students showed a different distribution of genotypes and allelic frequencies, compared to those found in the general Japanese population. Hence, the present study suggests that none of the major genetic polymorphisms in the RAA system strongly influence the onset of EH.     

The microsatellite alleles on chromosome 1 associated with essential hypertension and blood pressure levels

Essential hypertension (EH) is thought to be a polygenic disease. Several candidate genes of this disease have been investigated in studies using polymorphic genetic markers, but some studies have failed to show any association of EH with these genes. In this experiment, we used microsatellite markers on chromosome 1, and performed an association study between EH and control subjects. Genomic DNA was amplified with fluorescently labelled primers from the Applied Biosystems PRISM linkage mapping set HD-5 comprising 63 highly polymorphic microsatellite markers with an average spacing of 4.5 cM. We isolated three loci showing significant differences: D1S507, D1S2713 and D1S2842. The P-values of the allele with the greatest post hoc contributions in D1S507, D1S2713 and D1S2842 were 0.0008, 0.0062 and 0.0084, respectively. All these values were significant after Bonferroni correction. Furthermore, we found that the three microsatellite alleles were associated with the levels of systolic blood pressure. These data suggest that there are at least the three susceptibility loci for EH on chromosome 1, and that a case-control study using microsatellite markers on genomewide basis is a useful method for isolating the susceptibility loci of multifactorial disorders.     

Genetics of the kidney and hypertension

Success in the search for genes that cause or contribute to hypertension susceptibility has been limited to a few rare Mendelian forms of hypertension (glucocorticoid remediable aldosteronism, apparent mineralocorticoid excess, and Liddle’s syndrome). Our well-reasoned efforts to assess candidate genes in critical pathways known to be involved in blood pressure regulation have not been as productive in complex genetic cases of hypertension. These cases involve both genetic and environmental determinants. The most frequently used approach to the identification of hypertension genes involves genetic association studies, which are population based and compare cases and controls. Linkage analyses are also used but require family data. While much effort is spent identifying new markers and candidate genes, it is important to periodically determine which findings of linkage or association are confirmed in order to advance our quest to identify hypertension genes. In this review, the status of the assessment of the HSD11B2 gene is reviewed. In addition, data supporting the need to assess the mitochondrial genome, the other human genome, in hypertension susceptibility are reviewed.     

Corcoran Lecture. Cardiovascular genomics and oxidative stress

The majority of modifiable cardiovascular risk factors are complex, polygenic, or at least oligogenic traits, with genetic and environmental determinants playing important roles in disease risk and its phenotypic expression. The Human Genome Project and subsequent mouse and rat genome data have provided powerful tools to commence the dissection of genetic determinants of hypertension and other cardiovascular risk factors. Despite several new methodologies such as genome-wide scans, genome-wide gene expression profiling, and proteomic screens, it is fair to say that the progress of genetic studies designed as nonhypothesis driven has been relatively slow. On the other hand, several interesting candidate pathways have been identified, where investigators allowed for hypothesis-driven functional studies. One example of such pathway is vascular oxidative stress with its extensive network of genes and proteins, many with proven contributions to cardiovascular disease. Therefore, in parallel to genome-wide or proteome-wide studies, it will be constructive to pursue "pathwayomics" defined here as functional studies of a candidate pathway for disease pathogenesis.     

血压的性别差异及其生物学意义

目的 原发性高血压是世界上公认的多基因疾病.尽管人类基因组计划的完成大大加快了许多单基因疾病的基因的鉴定,但与原发性高血压相关基因的克隆仍然是生物医学研究面临的巨大挑战,其日益高涨的发病率及心血管并发症的高死亡率向人们提出了一个非常紧迫的问题,即怎样才能有效鉴定原发性高血压这个多基因疾病的相关基因.早在一百多年前,研究者就发现高血压有着明显的性别差异.并且,在许多少数民族人群中,男性与女性相比,不仅有着有着较高的平均生理血压值,而且还有着较高的高血压发病率.使男性有着较高生理血压值的基因或遗传多态性可能是高血压的易感因素,而激素相关基因或印迹基因则被认为参与了生理血压和高血压的性别差异的形成.此外,在临床实践中,血压的性别差异对促高血压药物或抗高血压药物的反应也有着显著的临床意义.因此,较好地了解血压的性别差异的分子遗传学可以有效地完成高血压形成相关基因鉴定,并最终促进高血压病的诊断和治疗的发展.本文主要揭示了血压的性别差异现象及其在基础血压研究和高血压相关的临床实践中的影响.

Abstract：

The ever-increasing incidence of hypertension and the high death rate of cardiovascular diseases raise an issue of how to efficiently identify genes associated with the polygenic diseases of hypertension. Significant gender differences in hypertension have been recognized over one hundred years. Males have higher average values of blood pressure as well as higher incidence of hypertension as compared to females in many ethnic groups. Genes or genetic polymorphisms governing the higher normal value of blood pressure in males may be the susceptible factors of hypertension. Hormone related genes or imprinting genes are considered as involvement in the development of gender differences of normal blood pressure and hypertension. The gender differences in responding to pro-hypertensive or anti-hypertensive agents have clinical implications in clinical practice. Additionally, better understanding the molecular genetics of normal blood pressure differences between genders may yield the identification of genes associated with the development of hypertension and eventually benefit to the diagnosis and therapeutics of hypertension.